Sensitivities and Dependencies of BRAF Mutant Colorectal Cancer Cell Lines with or without PIK3CA Mutations for Discovery of Vulnerabilities with Therapeutic Potential

被引:3
|
作者
Voutsadakis, Ioannis A. [1 ,2 ]
机构
[1] Sault Area Hosp, Algoma Dist Canc Program, 750 Great Northern Rd, Sault Ste Marie, ON P6B 0A8, Canada
[2] Northern Ontario Sch Med, Div Clin Sci, Sect Internal Med, Sudbury, ON P3E 2C6, Canada
来源
MEDICINA-LITHUANIA | 2022年 / 58卷 / 10期
关键词
colon cancer; cell line models; dependencies; targeted therapy; signal transduction; GENOMIC LANDSCAPE; EXPRESSION; SPECIFICITY; ENCORAFENIB; ACTIVATION; CETUXIMAB; PATHWAY; ARK5;
D O I
10.3390/medicina58101498
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Colorectal cancer represents a common malignancy and remains incurable in the metastatic stage. Identification of molecular alterations that are present in colorectal cancer has led to the introduction of targeted therapies that improve outcomes. BRAF and PIK3CA mutations are observed in a subset of colorectal cancers. Colorectal cancers bearing BRAF mutations may be treated with specific BRAF inhibitors. These drugs benefit patients with BRAF mutant colorectal cancers but responses are rather brief, and progression is the rule. In contrast, no PI3K inhibitors have proven successful yet in the disease. Thus, new treatments to supplement the currently available drugs would be welcome to further improve survival. Methods: Profiled colorectal cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were examined for BRAF and PIK3CA mutations and were interrogated for molecular characteristics and concomitant alterations that mirror clinical sample alterations. The Genomics of Drug Sensitivity in Cancer (GDSC) project was used for determination of drug sensitivities of BRAF mutated colorectal cell lines with or without concomitant PIK3CA mutations. The Cancer Dependency Map project served as the basis for identification of molecular dependencies and vulnerabilities in these cell lines. Results: CCLE includes 84 colorectal cancer cell lines, which recapitulate the molecular landscape of colorectal cancer. Of these, 23 and 24 cell lines possess BRAF and PIK3CA mutations, respectively. Seven BRAF mutant cell lines have V600E mutations and 14 PIK3CA mutant cell lines have hotspot helical or kinase domain mutations. V600E BRAF mutant cell lines with or without hotspot PIK3CA mutations are heterogeneous in their MSI status and mimic colorectal cancer tissues in other prevalent abnormalities including APC and TP53 mutations. Essential genes for survival include CTNNB1, WRN, and pyrimidine metabolism enzyme CAD. Besides BRAF mutations, BRAF inhibitor sensitivity in colorectal cancer cell lines is conferred by SACS mutations and PRKN locus loss. Conclusions: Colorectal cancer cell lines bearing the frequent BRAF and PIK3CA mutations present many alterations of the parental cancer tissue. Described vulnerabilities represent leads for therapeutic exploration in colorectal cancers with the corresponding alterations.
引用
收藏
页数:15
相关论文
共 50 条
  • [41] Synergistic actions of Alpelisib and Melatonin in breast cancer cell lines with PIK3CA gene mutation
    de Godoy, Bianca Lara Venancio
    Moschetta-Pinheiro, Marina Gobbe
    Chuffa, Luiz Gustavo de Almeida
    Ponde, Noam Falbel
    Reiter, Russel J.
    Colombo, Jucimara
    Zuccari, Debora Aparecida Pires de Campos
    LIFE SCIENCES, 2023, 324
  • [42] Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models
    Davis, S. Lindsey
    Robertson, Kelli M.
    Pitts, Todd M.
    Tentler, John J.
    Bradshaw-Pierce, Erica L.
    Klauck, Peter J.
    Bagby, Stacey M.
    Hyatt, Stephanie L.
    Selby, Heather M.
    Spreafico, Anna
    Ecsedy, Jeffrey A.
    Arcaroli, John J.
    Messersmith, Wells A.
    Tan, Aik Choon
    Eckhardt, S. Gail
    FRONTIERS IN PHARMACOLOGY, 2015, 6
  • [43] Heterogeneity of Epidermal Growth Factor Receptor Status and Mutations of KRAS/PIK3CA in Circulating Tumor Cells of Patients with Colorectal Cancer
    Gasch, Christin
    Bauernhofer, Thomas
    Pichler, Martin
    Langer-Freitag, Sabine
    Reeh, Matthias
    Seifert, Adrian M.
    Mauermann, Oliver
    Izbicki, Jakob R.
    Pantel, Klaus
    Riethdorf, Sabine
    CLINICAL CHEMISTRY, 2013, 59 (01) : 252 - 260
  • [44] Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients
    Sclafani, Francesco
    Wilson, Sanna Hulkki
    Cunningham, David
    De Castro, David Gonzalez
    Kalaitzaki, Eleftheria
    Begum, Ruwaida
    Wotherspoon, Andrew
    Capdevila, Jaume
    Glimelius, Bengt
    Rosello, Susana
    Thomas, Janet
    Tait, Daina
    Brown, Gina
    Oates, Jacqui
    Chau, Ian
    INTERNATIONAL JOURNAL OF CANCER, 2020, 146 (01) : 94 - 102
  • [45] Development of a multiplex allele-specific qPCR approach for testing PIK3CA mutations in patients with colorectal cancer
    Oscorbin, Igor P.
    Beginyazova, Oguljan P.
    Khlistun, Inna V.
    Shamovskaya, Darya V.
    Oskina, Natalia A.
    Filipenko, Maxim L.
    HELIYON, 2022, 8 (11)
  • [46] Solid Organ Transplantation Is Associated with an Increased Rate of Mismatch Repair Deficiency and PIK3CA Mutations in Colorectal Cancer
    Christenson, Eric S.
    Lee, Valerie
    Wang, Hao
    Yarchoan, Mark
    De Jesus-Acosta, Ana
    Azad, Nilo
    Gurakar, Ahmet
    Lin, Ming-Tseh
    Le, Dung T.
    Brennan, Daniel C.
    Jaffee, Elizabeth M.
    Bever, Katherine
    CURRENT ONCOLOGY, 2023, 30 (01) : 75 - 84
  • [47] High resolution melting analysis of KRAS, BRAF and PIK3CA in KRASexon 2 wild-type metastatic colorectal cancer
    Joana G Guedes
    Isabel Veiga
    Patrícia Rocha
    Pedro Pinto
    Carla Pinto
    Manuela Pinheiro
    Ana Peixoto
    Maria Fragoso
    Ana Raimundo
    Paula Ferreira
    Manuela Machado
    Nuno Sousa
    Paula Lopes
    António Araújo
    Joana Macedo
    Fernando Alves
    Camila Coutinho
    Rui Henrique
    Lúcio L Santos
    Manuel R Teixeira
    BMC Cancer, 13
  • [48] Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing-based cohort study
    Jauhri, Mayank
    Bhatnagar, Akanksha
    Gupta, Satish
    Bp, Manasa
    Minhas, Sachin
    Shokeen, Yogender
    Aggarwal, Shyam
    TUMOR BIOLOGY, 2017, 39 (02)
  • [49] Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan- and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer
    Hiroshi Soeda
    Hideki Shimodaira
    Mika Watanabe
    Takao Suzuki
    Makio Gamoh
    Takahiro Mori
    Keigo Komine
    Noriyuki Iwama
    Shunsuke Kato
    Chikashi Ishioka
    International Journal of Clinical Oncology, 2013, 18 : 670 - 677
  • [50] Combination of TNF-α and graphene oxide-loaded BEZ235 to enhance apoptosis of PIK3CA mutant colorectal cancer cells
    Cao, Yuhua
    Chong, Yu
    Shen, He
    Zhang, Mengxin
    Huang, Jie
    Zhu, Yimin
    Zhang, Zhijun
    JOURNAL OF MATERIALS CHEMISTRY B, 2013, 1 (41) : 5602 - 5610